Chronic Prostatitis (CP) and Chronic Pelvic Pain Syndrome (CPPS) are defined as “the presence of genitourinary pain in the absence of uropathogenic bacteria detected by standard microbiological methodology” (National Institutes of Health Summary Statement. National Institute of Health/National Institute of Diabetes, Digestive and Kidney Disease workshop on Chronic Prostatitis. Executive Summary, Bethesda, Md. December 1995). It is a chronic condition, of unknown origin, characterized by symptoms of pelvic pain, and lower urinary tract symptoms (LUTS) including both obstructive and irritative symptoms. It is characterized by lack of culture on urine and expressed prostatic secretion. Terminology defining CP was established by the Chronic Prostatitis Collaborative Research Network (CPCRN)[Krieger, J. N., L. Nyberg, Jr., and J. C. Nickel, NIH consensus definition and classification of prostatitis. JAMA, 1999. 282(3): p. 236-7.]. CP is classed as type III prostatitis, divided into inflammatory (IIIa) and non-inflammatory (IIIb or chronic pelvic pain—CPP). The term CP/CPP is therefore used collectively to describe this type III category, as symptomatically these patients are similar.
Prevalence rates of CP vary from 10 to 14% of men (Nickel, J. C., et al., Prevalence of prostatitis-like symptoms in a population based study using the National Institutes of Health chronic prostatitis symptom index. J Urol, 2001. 165(3): p. 842-5) having clinically confirmed disease, although the number is likely higher than this due to under or mis-diagnosis, commonly as recurrent urinary tract infection, overactive bladder or LUTS secondary to BPH. CP has a significant impact on quality of life, affecting travel, family relationships, and employment, as well as being associated with depressive symptoms. It also has significant economic impact.
There are few well performed, placebo-controlled, randomized trials of therapies aimed at CP, and treatment often consists of a multimodal trial-and-error approach. Fourteen major multi-center trials have reported in the last 5 years, sponsored by the NIDDK. These have included studies on antibiotics, alpha blockers, one anti-inflammatory (rofecoxib), Finasteride, and alternative therapies such as Quercertin. These studies are summarized in the review by Dimitrakov et al (Dimitrakov, J. D., et al., Management of chronic prostatitis/chronic pelvic pain syndrome: an evidence-based approach. Urology, 2006. 67(5): p. 881-8). Of particular interest were a placebo controlled 4-arm trial of ciprofloxacin, tamsulosin or combination thereof which showed no evidence of efficacy (Alexander, R. B., et al., Ciprofloxacin or tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome: a randomized, double-blind trial. Ann Intern Med, 2004. 141(8): p. 581-9), and a placebo controlled trial of rofecoxib (Nickel, J. C., et al., A randomized, placebo controlled, multicenter study to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial prostatitis. J Urol, 2003. 169(4): p. 1401-5) which did show positive responder rates.
No single etiology has been identified, and it is most likely a multifactorial process with several urologic insults causing a self-perpetuating process. It is postulated that a combination of inflammatory, immune, endocrine, neurological, epithelial dysfunction and psychological factors play a role in its pathogenesis.
Nerve Growth Factor (NGF) is one of the few neurological factors to show correlation with the pain of CP (Miller, L. J., et al., Urology, 2002. 59(4): p. 603-8). NGF has a role in the regulation of nociceptive nerves, including C-fibers. These are involved in pain transmission and also innervate mast cells, for which NGF is also a potent stimulator, causing mast cell degranulation. During mammalian development, NGF is required for the survival and growth of several populations of neurons.
Intravesical NGF is known to sensitize bladder afferent fibres (Dmitrieva, N. and S. B. McMahon, Pain, 1996. 66(1): p. 87-97). In men with CP, seminal NGF is the only inflammatory marker shown to positively correlate with levels of pain (Miller, L. J., et al. Urology, 2002. 59(4): p. 603-8) In the view of Steers et al, therapies based on altered NGF levels represent a promising avenue of investigation (Steers, W. D. and J. B. Tuttle, Nat Clin Pract Urol, 2006. 3(2): p. 101-10). However the authors do not teach which particular therapies would represent further investigation and certainly do not report or suggest the use on an anti-NGF antibody in treating pain and/or lower urinary tract symptoms associated with the condition.
There is a need to provide a novel, effective treatment for pain and/or lower urinary tract symptoms associated with chronic prostatitis and/or chronic pelvic pain syndrome without the adverse effects or limited efficacy of currently available therapies.
The anti-NGF antibody E3 has previously been reported as being useful in the treatment of chronic nociceptive and inflammatory pain, including rheumatoid arthritis pain, osteoarthritis pain and post-surgical pain (see for example WO2004/058184). However, given the complex etiology of chronic prostatitis, an example of chronic visceral pain, it cannot be predicted that an anti-NGF antibody, such as antibody E3, could be used for treating pain and/or lower urinary tract symptoms (LUTS) associated with chronic prostatitis and/or chronic pelvic pain syndrome.